Despite significant progress in identifying important mechanisms underlying HIV-1 pathogenesis, the role of host and viral factors contributing to progression to disease are still poorly understood. There is growing evidence supporting the hypothesis that differences in HIV/SIV coreceptor usage, and the host response to early infection are critical determinants of HIV-1 transmission and AIDS pathogenesis. The natural host species for SIV displays an unusual feature; lack of SIV-induced AIDS. A major focus of this proposal is to develop a differential model for pathogenesis. SIVagm infection in African green monkeys (Agms) does not result in clinical disease however, infection of pigtailed macaques (Ptm) results in classical T cell depletion and AIDS. Like HIV-1, most SIVagm and SIVsm strains utilize CD4 and CCR5 for viral entry, thus targeting these cells for infection and killing. Our studies have shown that there is a high level of viremia both in the plasma and cerebrospinal fluids of naturally infected monkeys however, the number o infected cells was generally lower than SIV infected macaques. Moreover, studies in the natural host have failed to correlate cellular immune responses with viral replication in the natural host. We have also shown that the CD4+CCR5+ T cell pool in PBMC of Agm is at least 5 fold lower than in Ptm suggesting fundamental differences in the size of the susceptible T cell pool may lead to profound differences in cell killing and by extension, cell-mediated killing. In this application, we propose to: l. Determine if host-specific differences in receptor/coreceptor expression at anatomically relevant sites of viral replication are a factor in the differential pathogenesis of SIVagm. 2. Determine if SIVagm strains with broader cell tropism (R5X4) will alter pathogenesis in Agm and Ptm. We will also compare neurotropic SIVagm (R5) strains in terms of cell tropism, evolution in the central nervous system and define pathogenic outcomes. 3. Determine if host-specific differences in cellular immune responses at anatomic sites for viral replication are a factor in SIVagm pathogenesis. We will examine longitudinally, cell- mediated immunity in the natural and unnatural host. In summary, this proposal seeks to understand the role of coreceptor expression, viral replication and cellular immunity in the pathogenesis of SIV.